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Intravenous iron: From anathema to standard of care

Michael Auerbach,1* Dan Coyne,2 and Harold Ballard3

A growing body of literature supports the use of intravenous iron as a compliment to erythropoiesis stimu-
latory therapy and in a signicant number of disease states where iron is necessary and oral iron is ineffec-
tive or not tolerated. The differences in efcacy, safety, and clinical nature of serious adverse events that
occur with the various iron preparations are poorly understood. Misinterpretation of adverse events leads
to underutilization of this important treatment modality. Understanding the history of the development and
use of intravenous iron is crucial to appreciate its importance in the management of anemias of dialysis,
cancer, and cancer chemotherapy and properly assess side effects and toxicity. The benets seen with
intravenous iron therapy are independent of the pretreatment levels of serum ferritin, iron, total iron binding
capacity, and percent transferrin saturation. Intravenous iron has been shown to overcome hepcidin
induced iron restricted erythropoiesis in iron-replete patients. Available clinical and experimental data
suggest that increased utilization of intravenous iron should be considered. Am. J. Hematol. 83:580588,
2008. V C 2008 Wiley-Liss, Inc.

Iron has been used by physicians throughout history. It Nonetheless, for over 50 years, recommendations for use
is believed that Sydenham, in 1681, was the rst to rec- of parenteral iron have been supported by little more than
ognize the value of iron therapy in chlorosis [1]. This im- folklore. Today, despite numerous publications to the con-
portant insight had little impact on medical practice. trary, medical students around the world are routinely
Although it was well-known at the beginning of the eight- taught that oral iron is the method of choice for replenishing
eenth century that chlorosis represented a lack of hemo- iron. Standard texts advise against the use of parenteral
globin and that iron was present in hemoglobin, it was iron unless the situation is life threatening or severe malab-
not until the nineteenth century that a French physician, sorption is present [9]. Until recently IM iron was consid-
Pierre Blaud, introduced pills containing ferrous sulfate ered the standard method of administration of parenteral
and reported the cure of chlorosis [2]. Early clinical expe- iron, despite excellent data in the Indian literature support-
rience with parenterally administered iron (intramuscularly ing IV irons superiority [10]. IM iron is painful, associated
and subcutaneously) has been summarized by Stockman with gluteal sarcomas [11,12], causes permanent discolora-
[1]. Heath et al. [3] injected subcutaneous and intramus- tion of the skin, and has never been shown to be less toxic
cular (IM) iron solutions and noted increases in hemoglo- or more efcacious than IV iron; therefore, it should be
bin levels in hypochromic anemias. The increased synthe- abandoned [13].
sis of hemoglobin was proportional to the amount of iron Prior to 1992, Imferon, manufactured by Fisons Pharma-
delivered. ceuticals in Homes Chapel England, was the only paren-
Parenteral iron usage in the early twentieth century was teral product available in the United States. The drug was
extremely limited and thought to have prohibitive toxic marketed by Merrill in the United States and was consid-
reactions. To probe the safety issue, Goetsch et al. [4] ered a minor product. In 1980, Hamstra et al. [14] pub-
introduced intravenous (IV) infusions of colloidal ferric hy- lished a review of their experience with the usage of IV iron
droxide as therapy for patients with hypochromic anemias. dextran in a cohort of approximately 500 patients with iron
Toxic reactions were severe in most instances and led to deciency and with no clinical reason to suggest that oral
the conclusion to preclude its use for therapeutic pur- administration would not be adequate. The dose and
poses except under most unusual circumstances. Subse- schedule varied from patient to patient. Virtually all patients
quent studies by Nissim [5] utilizing IV solutions of ele- achieved clinical benet. Three serious acute and eight
mental iron as saccharide led to the conclusion that delayed adverse events occurred, none of which were fatal.
parenteral iron as saccharide could be administered with All acute reactions were classied as anaphylactoid even in
relative safety and was more suitable than the ferric
hydroxide for this purpose. Clinical use of parenteral iron
accelerated with the iron saccharides in the 1940s and 1
Division of Hematology and Oncology, Private Practice Baltimore Maryland,
shortly thereafter with iron dextran. In 1954, a solution of Clinical Professor of Medicine, Georgetown University School of Medicine,
iron dextran (Imferon, Fisons pharmaceuticals) was intro- Washington, DC; 2Division of Nephrology, Professor of Medicine, Washing-
duced by Baird and Padmore [6] for the treatment of ton University School of Medicine, St. Louis, Missouri; 3Division of Hematol-
ogy and Oncology, Clinical Professor of Medicine, New York University
selective iron deciency anemias by the IM route. Used School of Medicine, Harborview VA Medical Center, New York, New York
IM and occasionally IV, in divided doses, it soon gained
acceptance as it was associated with rapid hematologic *Correspondence to: Dr. Michael Auerbach, Private Practice Baltimore Mary-
land, Clinical Professor of Medicine, Georgetown University School of Medi-
responses and a low incidence of adverse events. Since cine, Washington, DC. E-mail: mauerbachmd@aol.com
the 1990s, an upsurge in the clinical use of parenteral
Received for publication 12 October 2007; Revised 25 December 2007;
iron followed the introduction of recombinant human Accepted 2 January 2008
erythropoietin (EPO) for the correction of anemia in Am. J. Hematol. 83:580588, 2008.
patients with renal failure. Two recent papers validate the Published online 29 January 2008 in Wiley InterScience (www.interscience.
safety and efcacy of IV iron in the management of wiley.com).
patients who are iron decient [7,8]. DOI: 10.1002/ajh.21154

V
C 2008 Wiley-Liss, Inc.

American Journal of Hematology 580 http://www3.interscience.wiley.com/cgi-bin/jhome/35105


TABLE I. Currently Available Intravenous Iron Preparations [19]a,b,c,d

Low-molecular High-molecular Iron Ferric


weight iron dextran weight iron dextran saccharate gluconate

Test dose required Yes Yes No No


Vial volume (mL) 2 12 5 5
Mg iron (mg/mL) 50 50 20 12.5
Black-box warning Yes Yes No No
Total-dose infusion (TDI) Yes Yes No No
Premedication TDI only TDI only No No
Preservative None None None Benzyl alcohol
Molecular weight measured by manufacturer (Da) 165,000 265,000 3460,000 289440,000
a
INFeD [prescribing information]. Morristown, NJ: Watson Pharma Inc; 2001.
b
DexFerrum [prescribing information]. Shirley, NY: American Regent Laboratories Inc; 2001.
c
Venofer [prescribing information]. Shirley, NY: American Regent Laboratories Inc; 2001.
d
Ferrlecit [prescribing information]. Morristown, NJ: Watson Pharma Inc; 2001.

the absence of tachycardia, hypotension, or respiratory dis- drate inuences the strength of the iron complex determin-
tress. Hamstra concluded that anaphylactoid reactions are ing the rate of release of bioactive iron.
serious and unpredictable and opined that IV iron dextran
should be used only when iron deciency anemia cannot Clinical use of intravenous iron
be treated adequately with oral iron. The package insert for In 1988, Auerbach et al. [17] published a study evaluating
Imferon had a black box warning about the potential for an- acute and delayed reactions in anemic patients with absence
aphylaxis and a test dose was required. of bone marrow hemosiderin receiving a total dose infusion
(TDI) of high molecular weight iron dextran (HMW ID). Doses
Parenteral iron preparations ranged from 1,000 to 3,000 mg. The total dose of iron dextran
The adverse effects of bioactive free iron resulting from was diluted in 500 ml of normal saline and infused over 412
parenteral iron administration have been recognized for hr after a test dose of the diluted solution. There was no rela-
more than 50 years. This prompted the development of for- tionship between the infusion rate and adverse event fre-
mulations that shielded iron. The currently available IV prep- quency or severity. Subsequently the more rapid rate was
arations are all ironcarbohydrate complexes or colloids recommended. One of 87 patients experienced an acute,
based on small spheroidal ironcarbohydrate particles. nonfatal, anaphylactic reaction. Approximately half of the
Each particle consists of a core made of an iron-oxyhydroxy patients developed arthralgias and myalgias within the rst
gel surrounded by a shell of carbohydrate that stabilizes the 48 hr following infusion. Premedication with aspirin and
gel, slows the release of iron, and maintains the resulting diphenhydramine had no effect on the incidence or severity of
particles in colloidal suspension [13,15]. The currently the arthralgias and myalgias. During the conduct of this study,
approved IV irons all share this structure but differ from a case report in Lancet, in 1983, of meningism [18] after a
each other by the size of the core and the identity and den- dose of IV iron led to a recall of the worlds supply of Imferon.
sity of the surrounding carbohydrate. The characteristics of A critical review of this article indicated that the patient had a
the four available preparations are listed in Table I. The mo- minor arthralgia/myalgia syndrome with headache and neck
lecular weight of the iron complex reects the size of the stiffness and recovered without residua. The subsequent
iron core and the surrounding carbohydrate. Reported mo- publication [17] recommended parenteral iron be given as a
lecular weights vary according to method of measurement. TDI, but generated little interest following the Lancet case
The strengths of the iron complex affect pharmacokinetic report and Hamstras warning about IV iron therapy. Although
characteristics of the IV irons relevant to therapeutic use. complete correction of hemoglobin decit in a subset of
The rate of release of bioactive iron is inversely related to seven of these patients with concomitant chronic inamma-
the strengths of the complex, the stronger the complex the tory disorders was an exciting and unanticipated nding, the
slower the release of the iron. The toxicological implication major inference taken from the 1988 paper by the medical
of this is that stronger complexes have a lower potential to community was the 50% incidence of arthralgias and myal-
supersaturate transferrin with subsequent free iron toxicity gias, a self-limiting harmless reaction that leaves no residua.
compared to the weaker complexes [16]. In 1998, Auerbach et al. [19] reported that 125 mg of methyl-
The different preparations all share the same metabolic prednisolone before and after TDI dramatically reduced the
fate. After IV injections, ironcarbohydrate complexes mix frequency and severity of arthralgias and myalgias (Table II).
with plasma and are phagocytosed in the reticuloendothe- As oral iron was inexpensive and nearly always effective if tol-
lial system. Within phagocytes, iron is released from the erated, physicians had little need or interest in a product,
ironcarbohydrate complex into a low molecular weight iron albeit quite safe and effective, that they had been taught and
pool. This iron is either incorporated by ferritin into intracel- believed had potentially life threatening complications.
lular iron stores or is released to the extracellular iron bind- In spite of the admonitions within the medical community
ing protein, transferrin, which delivers iron to the transferrin regarding the use of IV iron, Fisons continued marketing
receptors on the surface of erythroid precursors. The result- the product for those clinical situations where iron adminis-
ing internalization of the iron transferrin complex supplies tration as a TDI was indicated. On June 1, 1989, the FDA
iron for hemoglobin synthesis. approved recombinant human EPO for the correction of
In summary, IV iron preparations are ironcarbohydrate anemia in patients with chronic renal failure. Little did
complexes characterized by specic carbohydrates used for anyone realize the role IV iron would play in managing
complexing and shielding the iron. The specic carbohy- these patients. Amgen, the manufacturer of EPO, and the

American Journal of Hematology 581


TABLE II. Effect of Methylprednisolone on Incidence
of Reactions [19]

No. with No. with no


reaction (%) reaction (%) Total

Saline 16 (59%) 11 (41%) 27


Methylprednisolone 15 (29%) 36 (71%) 51
Total 31 (40%) 47 (60%) 78

A statistically signicant reduction in reactions is noted in the methyl-


prednisolone treated group. Odds ratio 5 3.491; 95% condence inter-
val: 1.3159.264.

medical community also did not appreciate or anticipate the


role of EPO in anemias related to cancer, gastrointestinal
disorders, systemic collagen diseases, and a host of other
anemias associated with chronic disease states. Hundreds
of thousands of dialysis patients world-wide lived with the Figure 1. Functional iron deciency induced in a patient by 50 U/kg of rHuEPO
given three times weekly (Figure adapted from Eschbach et al., 1987).
belief that extreme fatigue and exhaustion from severe ane-
mia due to EPO deciency could not be ameliorated with-
out chronic transfusions. Dialysis patients had a life expect-
ancy of less than 3 years. The availability of EPO should
have generated enormous hopefulness in the dialysis popu- short delay symptoms routinely abated without treatment
lation, but enthusiasm for its use was far from brisk. In and rechallenging did not precipitate recurrence. This harm-
1991, 2 years after EPOs approval, the mean hemoglobin less reaction was unreported until the publication of a
among US dialysis patients was still less than 10 g/dL, and recent review [13]. Unfortunately, this event continues to be
many patients were not receiving EPO therapy [20]. misconstrued as an anaphylactoid reaction prompting inter-
Causes of EPOs ineffectiveness were not well understood vention with drugs such as diphenhydramine and epineph-
and were thought to be due to bleeding, absolute iron de- rine, each of which is able to cause severe cardiovascular
ciency, or the presence of comorbid conditions (anemias of side effects. Although the National Comprehensive Cancer
chronic disease). Functional iron deciency, a situation Network guidelines suggest pretreatment with diphenhydr-
where iron stores are present but not readily available for amine and acetaminophen to help reduce the risk of
erythropoiesis, became an important area of research inter- adverse reactions [25], the use of antihistamines can cause
est. Currently there are no satisfactory tools to accurately vasoactive reactions that may be misinterpreted and are of-
assess a state of functional iron deciency. However, mea- ten attributed to the injected iron. Given the lack of efcacy
surement of the reticulocyte hemoglobin content appears for pretreatment with aspirin and diphenhydramine to
promising [21]. reduce the incidence or severity of the arthralgia-myalgia
The nephrology community, lead by the excellent reactions [17], it is reasonable to avoid premedication with
research of Eschbach and others, began to carefully exam- these agents [13]. This is corroborated by a study in 135
ine the use of IV iron in dialysis patients receiving EPO. In iron decient patients receiving LMW ID preceded by pre-
1987, Eschbach et al. [22] demonstrated the clinical ef- medication with cimetidine, dexamethasone, and diphen-
cacy of 1,000 mg of IV iron dextran in dialysis patients fail- hydramine. In this study, most AEs requiring therapy or
ing to respond to EPO at standard doses of 50 U/kg thrice cessation of treatment were associated with the premedica-
weekly despite serum ferritin values greater than 500 ng/ tion. No serious events related to LMW ID were seen [26].
mL. Prompt increases in hemoglobin levels were seen (Fig. Subsequent to the pioneering studies of Hamstra and
1). Subsequently, Fishbane et al. [23] showed that the num- Fishbane, many investigators studied the role of IV iron as
ber of patients on dialysis responding suboptimally to EPO a component of the management of anemia in dialysis
administration could be reduced from 3040% to less than patients. The most important impetus to the increased use
10% when concomitant IV iron was administered. In 1996, of IV iron as an adjunct to EPO therapy came from the
Fishbane et al. [24] published data on the safety and ef- NKF-KDOQI Clinical Practice Guidelines for the anemia of
cacy of low molecular weight iron dextran (LMW ID), a chronic renal failure [27], which recommended IV iron in
product not commercially available at the time. They preference to oral iron, maintaining serum ferritin >100 ng/
showed that signicant reductions in dosing and duration of mL, and not withholding iron as long as the serum ferritin
therapy with EPO could be achieved by the addition of IV was <800 ng/mL. Administration of IV iron to patients with
iron. They concluded that oral iron was not effective in this this ferritin level, usually considered the lower range for iron
population due to poor compliance and impaired absorp- overload states, contradicted conventional hematology
tion. They further concluded that IV iron given as 1,000 mg practice. To prevent iron overload, the guidelines also rec-
divided over 10 doses during sequential dialysis treatments ommended halting iron therapy if the transferrin saturation
resulted in a rapid improvement of erythropoiesis and exceeded 50%. The recommendation to withhold IV iron
replenishment of depleted stores. In a retrospective chart when ferritin was >800 ng/mL or transferrin saturation was
review, Fishbane noted a serious adverse event (AE) rate >50% were opinion-based, and considered a balance
of approximately 0.7% following iron dextran administration. between the efcacy of IV iron in these patients and the
Of great interest was a description of what appeared to be potential for iron overload. Several studies have failed to
an acute arthralgia and myalgia syndrome associated with identify a specic serum ferritin value in dialysis patients
the test dose. In 0.3% of patients acute onset of chest and that was predictive of a lack of response to IV iron, but
back pain without hypotension, tachypnea, tachycardia, these trials suffered from several design aws, including
wheezing, stridor, or periorbital edema occurred. After a lack of a proper control group [28]. IV iron dextran boluses

582 American Journal of Hematology


complementing EPO therapy became the standard of care increase serum ferritin to 200400 lg/L and/or iron satura-
in dialysis in the 1990s. Because of the perceived 0.3% AE tion up to 2535% before considering EPO. Aronoff et al.
rate, the black box warning remained in the package insert [36] reported repeated doses of iron sucrose in 665 hemo-
for all iron dextrans and a test dose was required. dialysis patients receiving EPO was well tolerated, including
Hundreds of thousands of dialysis patients derived enor- 80 patients (12%) considered intolerant to an iron dextran.
mous clinical benets and improvements were seen in Black box warnings do not appear in the package inserts of
energy, activity, appetite, cognition, sexual activity, and either ferric gluconate or iron sucrose. As a result, these
overall quality of life. For patients receiving EPO therapy two products have rapidly replaced iron dextran, and TDI
the average lifespan on dialysis improved to more than 4 because of little interest in nephrology except in patients
years. Imferon, Fisons HMW ID was the product routinely on peritoneal dialysis. These nondextran irons bind iron
utilized until 1991. At the same time it was shown that IV less avidly than dextran, and this is believed to account for
Imferon could be given with equal efcacy as TDI or dose and infusion rate dependent acute vasoactive reac-
repeated boluses [29], a contaminated batch of Imferon led tions to iron sucrose and ferric gluconate. Typical reactions
to a total US recall of the drug. Serendipitously, the LMW include low blood pressure, abdominal discomfort, and
ID used in the Fishbane et al. study (INFeD, Schein Phar- back pain, and resolve with cessation of the infusion and
maceuticalsnow Watson Pharmaceuticalsand interna- time. The current highest recommended dose for ferric glu-
tionally known as Cosmofer, Pharmacosmos, Denmark) conate is 125 mg IV push over 510 min (Ferrlecit pack-
was approved for clinical use in the United States. In 1991, age insert) and for iron sucrose, 200 mg IV push or 300
Fisons, using molecular blueprinting, compared their prod- mg over 2 hr. Doses greater than 300 mg are not recom-
uct, Imferon, to Scheins INFeD, and discovered that INFeD mended [37].
was a lower molecular weight iron dextran with less varia- In a review of the US Food and Drug Administration
bility of the dextran chains (personal communication with (FDA) database of spontaneous AE reporting, Chertow
Fisons). Subsequently, in 1991, a decision to cease US dis- et al. [38] found no signicant differences in life threatening
tribution of Imferon was made, and Imferon was perma- or fatal serious AEs when ferric gluconate and iron sucrose
nently removed from the marketplace in 1992. were compared to LMW ID, although these reports are
In February 1996, Dexferrum (American Regent Pharma- highly insensitive in as much as they reect only reported
ceuticals) a HMW ID similar to Imferon was approved and events and under-estimate actual reaction rates many-fold.
provided an alternative to INFeD. No randomized trial com- A follow-up analysis [39] examined reactions to iron su-
paring efcacy and toxicity of any of these three products crose, and concluded that the frequency of IV iron related
had been published. INFeD and Dexferrum replaced AEs with all products has decreased, and overall the rates
Imferon in Nephrology, with INFeD being the major product were extremely low. The reported incidence of serious AEs
in use. In 1997, INFeD became unavailable for a short pe- among LMW ID, ferric gluconate, and iron sucrose are simi-
riod of time, necessitating use of Dexferrum in many dialy- lar with an estimated incidence of <1:200,000. Similarly,
sis patients. During this time there was an 11-fold increase Fletes et al. [40] found an 8-fold higher AE rate associated
(Freedom of Information, FDA) in the number of serious with the use of HMW ID (Dexferrum) that could not be
AEs reported to the US Food and Drug Administration. In explained by differences in patient or facility characteristics.
1998, Case [30] published an article recommending that McCarthy et al. [41] reported a nearly 3-fold increase in
Dexferrum not be used, noting in 14 patients receiving AEs with HMW ID than with LMW ID. This suggests that
Dexferrum 4 patients (28.6%) developed severe reactions the incidence of acute reactions for iron dextran believed to
consisting of severe back and leg pain, urticaria, and short- be correct (0.3%) is related to the use of HMW ID and the
ness of breath. Subsequently two of the four were given rate with LMW ID is far lower.
InFed and had no reactions. Similar conclusions were pub- Subsequently, three studies [4244] comparing the ef-
lished by Mamula in children with inammatory bowel dis- cacy of safety of LMW ID and iron sucrose found no differ-
ease [31]. ences in efcacy or toxicity between the two iron prepara-
The nondextran IV irons, ferric gluconate and iron su- tions. These recent studies conict with earlier claims of
crose, have been considered to have a markedly lower seri- lower reactions rates to nondextran irons based on compar-
ous acute event rate than the iron dextrans. In 1999, Faich ison to historical controls or exposure of patients with prior
and Strobos [32] compared the spontaneous reports to the allergies to these new agents [33,45].
US and European Drug agencies of serious reactions to In the last decade three events occurred that would
iron dextrans and non-iron dextrans. They noted a signi- markedly affect the practice of IV iron administration. First,
cantly higher rate of reactions and 31 deaths attributed to the work of Abels, Glaspy, Henry, Gabrilove, Littlewood,
iron dextrans, while no deaths were attributed to the non- and others [4650], showed that EPO was of great benet
dextran irons. In 2002, Michael et al. [33] found a very low in correcting anemia in patients with cancer or receiving
reaction rate with ferric gluconate in 2,534 hemodialysis cancer chemotherapy. Second, ferric gluconate (Ferrlecit,
patients in a double-blind, placebo controlled, study in ferric Schein Pharmaceuticals) and iron sucrose (Venofer, Ameri-
gluconate nave patients. They also noted that patients hav- can Regent Pharmaceuticals), two products that had been
ing reactions to ferric gluconate did not exhibit an increase used extensively in Europe and Asia for years, were
in tryptase, a marker of mast cell degranulation [34]. An approved as parenteral iron supplements in the United
increase in tryptase would be expected if reactions were States. Third, studies [49,5254] proved that IV iron admin-
true anaphylaxis. They also compared those results to the istered with EPO for the anemia of cancer and cancer
published reaction rate to iron dextrans, and concluded that chemotherapy more than doubled the response rate com-
ferric gluconate was much safer than iron dextran. None of pared to EPO alone. All of these trials will be discussed
these papers were able to differentiate the reaction rate of later in the text.
HMW versus LMW iron dextran preparations.
A similarly low reaction rate has been reported in open Iron in anemias of chronic disease
label studies of iron sucrose. In 1996, Silverberg [35] Central to the development of the anemia of chronic dis-
showed that approximately 20% of dialysis patients could ease (ACD) is disturbed iron homeostasis characterized by
have anemia effectively treated with iron sucrose alone. He decreased absorption and prevention of recycling of iron
recommended administering sufcient iron sucrose to from the cells of the reticuloendothelial system. This results

American Journal of Hematology 583


Figure 3. Change in LASA scores from baseline to end point evaluation for the
Figure 2. Percentage of responders and nonresponders in each treatment group intent to treat population. Qol, quality of life; TDI, total dose infusion [51].
for the ITT population. Responders were patients who achieved a maximal Hb lev-
els 120 g/L or an increase in Hb of 20 g/L during the study. (a) P < 0.01 versus
no-iron group; (b) P < 0.01 versus oral iron group.

oncology community. Further, anemias in cancer and can-


in hypoferremia (low transferrin-bound iron) and resultant cer chemotherapy patients were not as severe as those in
iron restricted erythropoiesis. Proinammatory cytokines dialysis patients in the pre-EPO days. There was little rea-
are important contributors to the hypoferremia and anemia son to believe that IV iron would be less benecial in can-
seen in chronic diseases. In chronic inammatory states cer chemotherapy patients receiving EPO than in dialysis
iron acquisition by macrophages takes place mainly patients, yet IV iron, for all intents and purposes, was not
through erythrophagocytosis and the transmembrane trans- used in oncology patients until published data with iron
port of ferrous iron by the protein divalent metal transporter dextran [51] reported a signicant benet in hemoglobin
1 (DMT 1) [55]. The proinammatory cytokines interferon response, hematopoietic response, time to maximal
gamma, lipopolysaccharide, and tumor necrosis factor response, and quality of life variables when IV iron was
alpha upregulate DMT 1 expression resulting in an in- given to patients receiving EPO for anemia of cancer
creased uptake of iron into activated macrophages and chemotherapy when compared with oral iron or no iron
also induces the retention of iron in macrophages by down- (Figs. 2 and 3). These responses were independent of
regulating the expression of ferroportin. Consequently iron type of cancer, intensity of chemotherapy, and baseline
release from macrophages is blocked [56]. Ferroportin, a iron parameters (percent transferrin saturation and serum
transmembrane exporter of iron, is believed to be responsi- ferritin). However, in this study the entry criteria required
ble for the transfer of absorbed ferrous iron from duodenal a serum ferritin of less than 200 ng/mL or less than
enterocytes into the circulation [57]. Hepcidin, an iron regu- 300 ng/mL with a percent saturation of transferrin of 19.
latory acute phase protein, has been shown to have an im- Because of a perception that many of the patients were
portant role in the pathophysiology of ACD. Expression of truly iron decient this led to a criticism of the conclusions
hepcidin is induced by lipopolysaccharide and interleukin 6 that baseline iron status was not predictive of who would
and is inhibited by tumor necrosis factor alpha [58]. Hepci- benet from parenteral iron and that IV iron should be
din is believed to be involved in the diversion of iron trafc given to all patients receiving EPO for chemotherapy-
by decreasing duodenal iron absorption and blocking iron associated anemia. Subsequently, Henry et al. [61], using
release from macrophages. A recently identied gene, ferric gluconate as an adjunct to EPO therapy in cancer
hemojuvulin, may act in concert with hepcidin to induce chemotherapy patients, corroborated the previously pub-
these changes [59]. The net effect of these alterations in lished data. In this study, 187 patients receiving chemo-
iron homeostasis is a limitation of the availability of iron for therapy were randomized to receive EPO 40,000 U/wk
erythroid progenitor cells and impairment of their prolifera- and either no iron, oral iron as 325 mg ferrous sulfate
tion by negatively impacting on heme biosynthesis. thrice daily or IV ferric gluconate 125 mg per week. They
In summary, in anemias of chronic diseases, the increase showed that there was an increase in hemoglobin levels
in inammatory cytokines causes an increase in hepcidin of 2 g or more in signicantly more patients treated with
with a subsequent decrease in iron absorption. When IV ferric gluconate (73%) than in those treated with oral
inammatory cytokines are not present, hepcidin levels are iron (46%) and those not treated with iron (41%). These
much lower and GI absorption of oral iron can more freely two studies clearly suggest that using IV iron therapy
occur. This is supported by data in patients with hereditary increases the hematopoietic responses to EPO in cancer
hemochromatosis, where a mutated HFE gene decreases patients with anemia of cancer chemotherapy. In the Auer-
hepcidin levels and allows unimpeded iron absorption to bach study the only serious AE occurred in one of two
occur [60]. patients receiving HMW ID when LMW ID was not avail-
able. In the Henry study there were no serious AEs attrib-
utable to iron. The conclusions of these two studies were
Iron in the anemia of cancer and further supported by a recently published study in patients
cancer chemotherapy with lymphoproliferative malignancies, not on chemother-
The benet of EPO in cancer patients is compelling apy, with positive marrow hemosiderin treated with epoetin
[4650], yet the transfer of this enthusiasm for EPO beta randomized to receive no iron or IV iron sucrose
usage to the oncology community was slow to evolve. [52]. In the iron treated patients there was a statistically
Awareness of the degree of benet IV iron had on anemia signicant improvement in response compared to those
in the nephrology population was generally lacking in the not receiving IV iron. In a study presented at the 2007 an-

584 American Journal of Hematology


nual meeting of the American Society of Clinical Oncol- dextran in nondialysis settings. Using a rat model, Zager
ogy, Pinter et al. [50,54] randomized 396 chemotherapy et al. [67] showed increased cellular uptake and subse-
patients receiving darbepoietin every 3 weeks with either quent necrosis and decreased recovery of kidney cells in
200 mg of IV ferric gluconate or iron sucrose to darbe- rats receiving iron sucrose > ferric gluconate  iron dex-
poietin alone or with oral iron. A statistically signicant tran (Venofer, Ferrlecit, and INFeD respectively) (Fig. 4).
decreased number of transfusions were reported in the IV Agarwal et al. showed stimulation of proteinuria and lipid
iron arm (9 vs. 20). These data are corroborated in a peroxidation with iron sucrose in CKD patients [16]. They
study of 75 anemic patients receiving chemoradiation concluded our study raises some concerns regarding the
therapy for carcinoma of the cervix [53]. In this trial, use of IV iron preparations in general, and iron sucrose in
patients were randomized patients to receive no therapy particular. . . A recent comparative crossover study found
or 540 mg of IV iron saccharate in 200 mL of normal 100 mg over 10 min of iron sucrose, but not ferric gluco-
saline over an unspecied period longer than 30 min. nate, induced proteinuria and albuminuria [68]. While tran-
Patients were treated with platinum containing chemother- sient injury by iron sucrose may be outweighed by the ben-
apy plus radiation therapy to the pelvis. Those anemic at ets of iron repletion and repair of anemia, these results
presentation and randomized to the IV iron arm received should question the abandonment of LMW ID as rst line
the IV iron infusion at the beginning of therapy. IV iron therapy. Pai et al. [69] compared nontransferrin bound iron
was also given to those randomized to the IV iron arm not and markers of oxidative stress after single IV doses of iron
anemic at onset but developing anemia during therapy. dextran, ferric gluconate, and iron sucrose. They concluded
AEs with iron administration were not provided. None of iron sucrose and ferric gluconate were associated with
the patients in either arm received an ESA agent. Sixty- greater nontransferrin bound iron appearance when com-
four percent of the patients in the control arm and 40% of pared with iron dextran. However, only ferric gluconate
the patients in the IV iron arm were transfused. Unfortu- showed signicant increases in lipid peroxidation. Long
nately, there were signicant intragroup differences in this term studies assessing the risks and benets of different IV
study making interpretation of the results difcult. None- iron preparations are needed.
theless, this study, albeit underpowered, raises the ques- As of this review there exist no clear practice guidelines
tion of the benet of IV iron alone in decreasing transfu- for IV iron as an adjunct to ESA therapy outside nephrol-
sion requirements in patients receiving chemoradiation ogy. Randomized trial data have shown the efcacy of IV
therapy. iron in epoetin-treated patients, even among patients with
A soon to be published study lends support to the previ- elevated ferritin (5001,200 ng/mL) with TSAT  25%
ously cited studies. Pedrazolli et al. [62] enrolled 149 [70,71]. Among dialysis patients, who frequently have ele-
patients with solid tumors and at least 12 weeks of planned vated ferritin from inammation, reliable predictors of a
chemotherapy who were randomized to receive 150 mg of hematological response to IV iron have not been found
subcutaneously administered darbepoietin weekly alone or [71]. The nephrology literature is rife with publications
with IV ferric saccharate administered as 125 mg per week showing IV iron reduces ESA dose even in patients with
for the rst 6 weeks. This study was unique in its require- iron parameters consistent with an iron repletion state [28].
ment that excluded patients with ferritins < 100 ng/mL and These data are corroborated by publications in the oncol-
TSATs < 20%. They concluded in patients with chemother- ogy literature [51,52,54,61] in which hemoglobin response
apy related anemia and no iron deciency IV iron supple- occurs in patients with transferrin saturations as high as
mentation signicantly reduces treatment failures with dar- 50% [61] and in patients with positive marrow hemosiderins
bepoietin, without added toxicity. The use of IV iron is [52]. In the absence of formal evidenced based guidelines,
increasing in oncology but to date only iron dextran is and consistent with published data, we believe it is reason-
approved, despite the extensive use and safety record of able to recommend that IV iron be added to ESA therapy
ferric gluconate and iron sucrose in nephrology. A summary but avoid iron use if transferrin saturation approaches 50%.
of these studies is listed in Table III. The IV iron can be administered either as a TDI of LMW ID
or as repeated lower doses of LMW ID, ferric gluconate, or
Potential negative effects of intravenous iron iron sucrose. HMW ID dextran should not be used
Iron is a pro-oxidant, an important nutrient for many bac- [13,31,72].
teria, and has been shown to exacerbate sepsis in labora- In addition to optimizing efcacy of EPO in anemic dialy-
tory animals. Consequently, concerns have been raised sis and oncology patients, indications for IV iron as sole
that IV iron might increase oxidative stress, infections, anemia therapy are rapidly expanding. In a variety of clini-
mortality, or even tumor growth. Human studies have cal settings use of IV iron alone is being investigated to
shown transient increases in markers of oxidative stress reduce or eliminate red blood cell transfusions, or avoid
with all forms of IV iron [63]; however, use of IV iron in institution of costly EPO therapy. Entities in which IV iron
dialysis patients has been associated with comparable or has great potential for treating anemia and ameliorating
improved survival compared to no iron [64,65] in very transfusion need include: inammatory bowel disease,
large databases. Hoen et al. [66] prospectively examined small bowel malabsorption, gastric bypass surgery, obstet-
the risks for infection in 998 hemodialysis patients over 6 rics and gynecology, surgical blood loss, in those conditions
months. Central venous catheters, history of bacteremia, where intestinal blood loss exceeds the ability of the intes-
arteriovenous grafts, and immunosuppression were associ- tines to absorb adequate iron from oral ingestion (Osler-
ated with increased risk of infections, but not ferritin levels Weber-Rendu), and in patients who are intolerant of or
or total dose of IV iron administered. No study to date has unresponsive to oral iron. With the exception of HMW ID
contradicted these data. Lastly, in all published trials with any of the other three available preparations can be utilized
IV iron in oncology, there were no differences in tumor out- safely and effectively. For these conditions, when one con-
comes in those who received IV iron compared to ESAs siders cost and convenience, TDI of LMW ID is the pre-
alone. However, as of this review, there are no prospective ferred method of IV iron administration.
data with tumor outcome as a primary or secondary end- Improving anemia in chronically ill patients improves
point. quality of life. Small studies have found IV iron may improve
There are three studies suggesting that iron sucrose and quality of life independent of improvements in anemia
ferric gluconate may have more nephrotoxicity than iron [73,74]. Erythropoietic stimulatory agents offer a more

American Journal of Hematology 585


TABLE III. Overview of Studies of IV Iron in Oncology

586
Auerbach et al., 2004 Henry et al., 2007 Hedenus et al., 2007 Pinter et al., 2007 Kim et al., 2007

No. of Patients 157 187 67 398 75


Patient population Nonmyeloid malignancy receiving Nonmyeloid malignancy starting Lymphoproliferative malignancy, Nonmyleloid malignancy 8 weeks Cervical cancer receiving
chemotherapy cycle of chemotherapy no chemotherapy of planned chemotherapy chemoradiotherapy
Treatment arms IV iron versus oral iron versus no IV iron versus oral iron versus IV iron versus no iron IV iron versus no/oral iron IV iron versus no iron
iron no iron
Study period 6 weeks or until end bolus 9 weeks 16 weeks 16 weeks 6 weeks
treatments
Inclusion criteria Hb 10.5 g/dL <11 g/dL 911 g/dL <11 g/dL Hb measured prior to each
chemotherapy cycle: Hb 10
12 g/dL: pts in IV iron group
received iron; Hb < 10 g/dL:
pts in both groups were
transfused
Inclusion criteria SF  200 ng/mL or SF  300 SF  100 ng/mL or TSAT  15%; SF < 800 ng/mL, Stainable iron in SF < 800 ng/mL N/A
TSAT/SF ng/mL and TSAT  19% SF < 900 ng/mL and TSAT bone marrow
<35%
IV Iron dosing Iron dextran TDI or 100 mg to Ferric gluconate 125 mg QW for Iron sucrose 100 mg QW (week Ferric gluconate or iron sucrose Iron sucrose 200 mg if Hb
calculated dose 8 weeks 16) 100 mg Q2W (week 814) 200 mg Q3W 1012 g/dL
ESA dosing 40,000 U/wk Procrit no dose 40,000 U/wk Procrit, dose increase 30,000 U/wk neoRecormon dose 500 lg Q3W Aranesp dose None
adjustments permitted after 4 weeks; dose adjustments permitted reductions permitted
reduction permitted for safety
Hb CFB TDI: 2.4 g/dL, bolus IV iron: 2.5 g/ IV iron: 2.4 g/dL, oral iron: 1.6 g/ IV iron: 2.91 g/dL, no iron: 1.5 g/ N/A Similar change between IV iron
dL, oral iron: 1.5 g/dL, dL, no iron: 1.5 g/dL, evaluable dL; PP population and control groups
no iron: 0.9 g/dL, ITT population population
Hb response TDI: 68%, bolus IV iron: 68%, IV iron: 73%, oral iron: 45%, no IV iron: 93%, no iron: 53%, PP IV iron: 86%, no/oral iron: 73%, N/A
oral iron: 36%, no iron: iron: 41%, evaluable population population median time to Median, time to target Hb: 30
25%, ITT population achieve Hb response: 6 weeks days IV iron versus 43 days No/
IV iron versus 12 weeks no iron oral iron
ESA No dose adjustment permitted N/A At Wk 15, ave difference was N/A N/A
>10,000 U or 25% lower in IV
iron than no iron group
Transtusions TDI: 5 pts bolus IV iron: 4 pts, oral IV iron: 11 pts (18%), oral iron: 6 IV iron: 2 pts, Pts enrolled in study for at least 29 IV iron: 40% pts, No iron:
iron: 3 pts, no iron: 7 pts pts (10%), no iron: 14 pts (22%) no iron: 1 pt days: IV iron: 9%: no/oral iron: 64% pts
Tx given after rst 4 weeks: IV iron: 20% Mean transfusion volume:
2 of 11 pts; oral iron: 5 of 6 pts; IV iron: 1.87 units;
no iron: 7 of 14 pts No: 3.58 units
Energy/activity QOL  IV iron : LASA scores for Only IV iron group had signicant : N/A % pt achieving FACT-F  3 points: N/A
energy, activity and QOL in FACT-F score; difference IV iron: 62%; no/oral iron: 54%
 Oral iron small : energy, activity, began at 4 weeks while Hb
QOL response was still similar
between groups
 No iron ; energy, activity, QOL
from baseline

American Journal of Hematology


Figure 4. Cellular injury in cultured human proximal tubule cells after exposure to iron compounds P < 0.01 compared with control cells. (Zager et al. Am J Kidney Dis
2002;40:90103)

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